Aspartic proteases, including renin, β-secretase (BACE), HIV protease, HTLV protease and plasmepsins I and II, are implicated in a number of disease states. In hypertension, elevated levels of angiotensin I, the product of renin catalyzed cleavage of angiotensinogen are present. Elevated levels of β amyloid, the product of BACE activity on amyloid precursor protein, are widely believed to be responsible for the amyloid plaques present in the brains of Alzheimer's disease patients. The viruses HIV and HTLV depend on their respective aspartic proteases for viral maturation. Plasmodium falciparum uses plasmepsins I and II to degrade hemoglobin.
In the renin-angiotensin-aldosterone system (RAAS), the biologically active peptide angiotensin II (Ang II) is generated by a two-step mechanism. The highly specific aspartic protease renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called AT1 and AT2. Whereas AT1 seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown.
Modulation of the RAAS represents a major advance in the treatment of cardiovascular diseases (Zaman, M. A. et al Nature Reviews Drug Discovery 2002, 1, 621-636). ACE inhibitors and AT1 blockers have been accepted as treatments of hypertension (Waeber B. et al., “The renin-angiotensin system: role in experimental and human hypertension,” in Berkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). Interest in the development of renin inhibitors stems from the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. Renin inhibitors are not only expected to be superior to ACE inhibitors and AT1 blockers with regard to safety, but more importantly also with regard to their efficacy in blocking the RAAS.
Recently, non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; Maerki H. P. et al., Il Farmaco, 2001, 56, 21 and International Patent Application Publication No. WO 97/09311). Other non-peptide renin inhibitors have been described in International Patent Application Nos. PCT/US2005/03620 (WO2006/042150), PCT/US2007/008520, and PCT/US2006/043920 (WO2007/070201) and U.S. Provisional Patent Application Nos. 60/845,331 and 60/845,291), the disclosures of each of which are incorporated herein by reference. An example of such aspartic protease/renin inhibitors is a compound represented by Formula (A):
wherein the substituents: R1, R2, R3, R4, R5, R6, X1, Y1, Z, Q and G are as defined in PCT/US2006/043920 (WO2007/070201). Another example of an aspartic protease/renin inhibitor is a compound represented by Formula (A-1):
and more specifically a compound represented by Formula (A-2):
or a pharmaceutically acceptable salt thereof, wherein: R1 is H or alkyl; R2 is alkyl, cycloalkyl or cycloalkylalkyl; R3 is F, Cl, Br, cyano, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, or alkanesulfonyl; and n is 0, 1, 2, or 3.
The process of forming an aspartic acid protease inhibitor, e.g., represented by Formula (A-1) or (A-2), above, is exemplified in the following scheme:
Specific conditions for carrying out the above reactions are provided in PCT/US2006/043920 (WO2007/070201), the entire teachings of which are incorporated herein by reference.
Significant quantities of the pure aspartic protease/renin inhibitor are required in the drug development process, e.g., for in vitro and in vivo testing, as formulated and/or un-formulated drug substance. Accordingly, it would be useful to develop efficient processes for the large-scale preparation of such aspartic protease/renin inhibitor compounds and the intermediates used therein.